1. Field
The present disclosure relates generally to the fields of cell biology, developmental biology and medicine. More particularly, it concerns methods and compositions relating to the stimulation of progranulin expression and the treatment and prevention of frontotemporal lobar degeneration, resulting in frontotemporal dementia.
2. Description of Related Art
Frontotemporal dementia (FTD) is a clinical syndrome characterized by progressive deterioration of decision-making abilities, control of behavior, and language, with relative early sparing of memory. It is the second most frequent presenile dementia disorder, and ˜25% of the cases are hereditary (van Swieten and Heutink 2008). A common pathological manifestation of FTD is frontotemporal lobar degeneration with TDP-43 inclusions. FTD is a devastating and generally fatal disease. Median survival after diagnosis is 10 years (Hodges et al. 2003). Current treatment options are limited to management of emotional and behavioral aspects with antidepressants and social interventions (Kirshner 2010).
Familial cases of FTD are frequently caused by loss-of-function mutations of the GRN gene (van Swieten and Heutink 2008; Cruts et al., 2006; Baker et al., 2006 and Gass et al., 2006). The protein encoded by this gene, progranulin (also called GRN protein, human granulin precursor, proepithelin, acrogranin, and PC cell-derived growth factor), is a secreted glycoprotein with growth factor-like and immunomodulatory activities (Ahmed et al., 2007). It was recently identified as a TNF receptor antagonist (Tang et al., 2011). Progranulin contains one half-length and seven full-length granulin domains, which are released following proteolytic cleavage. Biological effects, including promotion of neuronal survival, neurite outgrowth, and regulation of microglial inflammatory responses, have been attributed to both the full-length protein and the granulin peptides (Eriksen and Mackenzie 2008).
To date, >60 pathogenic GRN mutations have been reported in patients with FTD, and all are expected to result in haploinsufficiency. Progranulin-deficient mice display dysregulated immune responses in the brain and recapitulate phosphorylated cytoplasmic TDP-43 aggregates seen in FTD brains (Yin et al., 2010). Furthermore, the concentration of progranulin in the serum is reported to be lower in patients and mutation carriers compared with healthy controls (Sleegers et al., 2009 and Finch et al., 2009), suggesting that reduced progranulin expression causes FTD. Therefore, increasing progranulin expression from the wild-type allele may prevent or slow down disease progression.
Following this rationale, Capell et al. (Capell et al., 2011) recently reported that alkalizing drugs and vacuolar ATPase inhibitors increase progranulin protein levels through a post-transcriptional mechanism. Since this mechanism likely involves reduced turnover or lysosomal conversion to mature granulins, the value of this approach for disease prevention or treatment is doubtful. Thus, identification of additional drugs that increase progranulin expression at the most proximal, i.e., transcriptional level is essential to slow down or reverse the cognitive decline of FTD will prove extremely valuable.